The Tshilo Dikotla Study: Metabolic Outcomes of Children HIV/ARV-Exposed Uninfected in Botswana

Tshilo Dikotla 研究：博茨瓦纳未感染 HIV/ARV 的儿童的代谢结果

• 批准号: 9235276
• 负责人: Jennifer Jao
• 金额: $ 64.54万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235276
• 关键词: 3 year old; Acquired Immunodeficiency Syndrome; Adverse effects; Affect; Africa; Africa South of the Sahara; Amino Acids; Anti-Retroviral Agents; Birth; Botswana; Branched-Chain Amino Acids; Child; Childhood; Country; Development; Diabetes Mellitus; Energy Metabolism; Environment; Exhibits; Exposure to; Fasting; Fetus; Future; Genus Hippocampus; Gestational Age; Glucose; HIV; HIV Infections; HIV antiretroviral; HIV-exposed uninfected infant; Health; High Prevalence; Infant; Institutes; Insulin; Insulin Resistance; Life; Link; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mother-to-child HIV transmission; Neonatal; Nevirapine; Outcome; Participant; Perinatal; Pharmaceutical Preparations; Phenotype; Population; Pregnant Women; Prevalence; Prevention; Prevention strategy; Prevention therapy; Prophylactic treatment; Prospective cohort study; Public Health; Randomized; Regimen; Reporting; Research; Research Infrastructure; Risk; Role; Small for Gestational Age Infant; Technology; Time; Translating; Vertical Disease Transmission; Vulnerable Populations; Woman; Work; Zidovudine; acylcarnitine; antiretroviral therapy; fetal; in utero; insulin sensitivity; metabolic abnormality assessment; metabolomics; mitochondrial dysfunction; neonatal exposure; postnatal; prenatal; primary outcome; public health relevance; screening; success; transmission process; treatment strategy; trend

 DESCRIPTION (provided by applicant): Expanding use of combination antiretroviral therapy (cART) for the prevention of mother-to-child transmission (PMTCT) of HIV has dramatically decreased vertical transmission rates to <2%. The overwhelming success of PMTCT has resulted in a diminishing population of children born with perinatally acquired HIV infection on the one hand, and a mounting number of HIV-exposed uninfected (HEU) children on the other hand. Currently an estimated 20% or more of all infants born in sub-Saharan Africa are born HEU. In utero HIV/antiretroviral (ARV) and postnatal ARV treatment are known to perturb energy metabolism and could have permanent effects on the future metabolic health of HEU infants, including the development of insulin resistance. Early maladaptive changes in mitochondrial function and intermediary metabolism in HEU children exposed to ARVs may be mediated in the intrauterine environment through changes in fetal metabolic programming, and thus, may impact metabolic outcomes in these children. Through our work, we have demonstrated that exposure to specific in utero and neonatal ARVs may affect insulin sensitivity and fuel substrate utilization more than other ARVs in HEU infants early in life. Long-term and mechanistic evidence is scarce, however, in this population, particularly in sub-Saharan Africa. This study investigates the impact of in utero and postnatal HIV/ARV exposure on the metabolic health of HEU infants/children. First, we will assess whether in utero and neonatal HIV/ARV exposure is associated with changes in insulin sensitivity in HEU children from birth to 3 years of life using HIV-unexposed uninfected (HUU) infants as a comparator group. In addition, we will evaluate whether specific neonatal ARV prophylaxis regimens differ in metabolic effects amongst HEU children. Second, we will use targeted metabolomics to evaluate whether specific intermediary metabolites (short chain acylcarnitines and branched-chain amino acids) reflect or contribute to changes in insulin sensitivity in HEU and HUU children. Third, we will explore the role of the mitochondria in insulin sensitivity and intermediary metabolism amongst HEU and HUU children in an effort to understand potential mechanisms and targets for future studies. Building on our previous work with HEU and HUU infants in Africa, we propose a new prospective cohort study with a nested randomized component in HIV-infected and -uninfected woman/child dyads in Botswana. If in utero and postnatal HIV/ARV exposures are found to contribute to derangements in intermediary metabolism such that insulin sensitivity is altered early in life and HEU children are at increased risk for insulin resistance later in life, this woud impact screening and prevention strategies for diabetes in this vulnerable population and argue for further research to identify pre- and postnatal ARV regimens with superior PMTCT efficacy, but with minimal adverse metabolic consequences to the exposed fetus or infant.

 描述（由申请人提供）：扩大使用联合抗逆转录病毒疗法（cART）来预防艾滋病毒母婴传播（PMTCT）已将垂直传播率显着降低至<2% PMTCT 取得了压倒性的成功。一方面，围产期感染 HIV 的儿童数量不断减少，另一方面，未感染 HIV 的儿童 (HEU) 数量不断增加，目前估计有 20% 或 20% 的儿童感染了 HIV。众所周知，在撒哈拉以南非洲地区出生的婴儿中，有更多的婴儿出生时就接受了艾滋病毒/抗逆转录病毒 (ARV) 治疗，而产后抗逆转录病毒治疗会扰乱能量代谢，并可能对 HEU 婴儿未来的代谢健康产生永久性影响，包括胎儿的发育。暴露于抗逆转录病毒药物的 HEU 儿童中线粒体功能和中间代谢的早期适应不良变化可能是通过胎儿代谢程序的变化在宫内环境中介导的，因此可能会影响代谢结果。通过我们的工作，我们已经证明，在生命早期，与其他抗逆转录病毒药物相比，在子宫内和新生儿中接触特定的抗逆转录病毒药物可能会更影响胰岛素敏感性和燃料底物利用，但长期和机制证据却很少。这项研究调查了子宫内和产后 HIV/ARV 暴露对 HEU 婴儿/儿童代谢健康的影响。 HIV/ARV 暴露与 HEU 儿童从出生到 3 岁的胰岛素敏感性变化相关，以未暴露于 HIV 的未感染 (HUU) 婴儿作为比较组。此外，我们将评估特定的新生儿 ARV 预防方案在代谢方面是否存在差异。其次，我们将使用靶向代谢组学来评估特定中间代谢物（短链酰基肉碱和支链氨基酸）是否反映或促成胰岛素的变化。第三，我们将探讨线粒体在 HEU 和 HUU 儿童胰岛素敏感性和中间代谢中的作用，以了解未来研究的潜在机制和目标。针对非洲婴儿，我们提出了一项新的前瞻性队列研究，其中对博茨瓦纳子宫内和产后 HIV/ARV 感染和未感染的妇女/儿童进行了嵌套随机研究。研究发现，暴露会导致中间代谢紊乱，从而导致生命早期的胰岛素敏感性发生改变，而 HEU 儿童在以后的生活中出现胰岛素抵抗的风险增加，这将影响这一弱势群体的糖尿病筛查和预防策略，并主张进一步采取措施。研究旨在确定产前和产后抗逆转录病毒疗法具有优越的 PMTCT 功效，但对暴露的胎儿或婴儿的不良代谢后果最小。